1-(n, n-dibenzylamino)-2-[n&#39;-(halo-loweralkanoyl)-n&#39;-(substituted)]-loweralkylenediamines



United States Patent 0 3,135,794 1 (N,N-DlBENZYLAh HN6)-2-{N (HALO LUWER- ALKANOYL) N (SUBSTITUTED)] LOWER- ALKYLENEDIATVHNES Sydney Archer, Bethlehem, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Original application Sept. 25, 1959, Ser. No. 842,203. Divided and this application Get. 18, 1960, Ser. No. 66,3?6

2 Claims. (Cl. 269-562) This invention relates to intermediates useful in the preparation of l-[l-, 2- or S-indolyl)-lower-alkyl]piperazines, l-[(l-, 2- or 3-indolyl)-lower-alkyl]homopiperazines, 1 [w- (3-indolyl)-w-hydroXy-lower-alkyl]piperazines and l-[m-(3-indolyl) -w-hydroXy-lower-a1kyl]homopiperazines.

3-indolyl-lower-alkylamines are known. The invention here resides in the concept of attaching a l-piperazinylloWer-alkyl group or a 1-homopiperazinyl-lower-alkyl group to the 1-, 2-, or 3-position of the indole nucleus or a l-piperazinyl-w-hydroXy-lower-alkyl group or a l-homopiperazinyl-w-hydroXy-loWer-alkyl group to the 3-position of the indole nucleus. It is also concerned with certain novel intermediates and with processes for making such intermediates and for making said l-[(1-, 2- and 3-indolyl)-lower-alkyl]piperazines, l-[(l-, 2- or 3-indolyl)- loWer-alkyl]homopiperazines, l [w (3-indolyl)-w-hydroxy-lower-alkyl]piperazines and 1-[w-(3-indolyD-w-hydroXy-lower-alkyl]homopiperazines.

A preferred aspect of my invention relates to 1-(N,N- dibenzylamino)-2-[N'-(uor fi-halo-lower-alkanoyl)-N'- (substituted)1-l0wer-alkylenediamines useful as intermediates in the preparation of compounds having the formulae:

wherein R is a hydrogen atom or one or more substituents selected from the group consisting of halogen (including fluorine, chlorine, bromine and iodine), loweralkyl, lower-alkoxy, hydroxy, methylenedioxy, ethylenedioxy, lower-alkylrnercapto, lower-alkylsulfinyl, loweralkyl-sulfonyl, trifluoromethyl, monocarbocyclic aryl-lower-alkoxy and lower-alkanoyloxy; R is a hydrogen atom r Ice or a lower-alkyl, hydroxy-lower-alkyl, monocarbocyclic aryl, monocarbocyclic aryl-loWer-alkyl, bis(monocarbocyclic aryl)-lower-alkyl, monocarbocyclic aryl-loweralkenyl or heteromonocyclic radical; R is a hydrogen atom or a lower-alkyl or monocarbocyclic aryl radical; R is a hydrogen atom or a lower-alkyl, monocarbocyclic aryl, monocarbocyclic aryl-lower-alkyl or a monocarbocyclic aryl-lower-alkenyl radical; R and R are hydrogen atoms or each of R and R can represent a lower-alkyl radical or one of R and R can represent a lower-alkyl radical While the other of R and R represents a hydrogen atom; X is a hydrogen atom or the hydroxyl radical and represents the hydroXyl radical only when the hydroxyl radical and the l-nitrogen atom of the piperazine ring are separated by at least two carbon atoms, that is when n in Formula la is at least 2; n represents an integer from one to seven; and m represents the integers l to 2.

In the above general Formulae la, b and 0, R represents a hydrogen atom or one or more substituents selected from the group consisting of halogen, lower-alkyl,

lower-alkoxy, hydroXy, methylenedioxy, ethylenedioxy',

lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, trifluoromethyl, monocarbocyclic aryl-loWer-alkoxy and lower-alkanoyloxy. R can represent from one to four of the above substitutents which can be on any of the four available positions on the benzene ring, and when more than one substituent is present, they can be the same or dififerent. When R represents a lower-alkyl, lower-alkoxy, lower-alkylmercapto, lower-alkyl-sulfinyl, lower-alkylsulfonyl or lower-alkanoyloxy radical, it can be either straight or branched and can contain from one to about five carbon atoms, and when R represents a monocarbocyclic aryl-lower-alkoxy radical, it can contain from seven to about ten carbon atoms and can be further substituted by from one to about three substituents of the nature named above, i.e., halogen, lower-alkyl, loweralkoxy, hydroxy, methylenedioxy, ethylenedioxy, loweralkyl-mercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, trifinoromethyl and lower-alkanoyloxy. R thus stands, inter alia, for fluoro, chloro, bromo, iodo, methyl, ethyl, butyl, methoxy, dimethoxy, trimethoxy, ethoxy, ethoxymethoxy, butoxy, hydroxy, mcthylenedioxy, ethylenedioxy, methylmercapto, isopropylmercapto, methylsulfinyl, isopropylsulfinyl, methylsulfonyl, isopropylsulfonyl, trifluoromethyl, benzyloxy, 3,4,5-trimethoxybenzyloxy, acetoxy or isobutyryloxy.

In the above general Formulae, la, b and 0, R represents a hydrogen atom or a loWer-alkyl, hydroXy-loweralkyl, monocarbocyclic aryl, monocarbocyclic aryl loweralkyl, bis (monocarbocyclic aryl)-lower-alkyl, monocarbocyclic aryl-lower-alkenyl or heteromonocyclic radical; R represents a hydrogen atom or a lower-alkyl or monocarbocyclic aryl radical; and R represents a hydrogen atom or a lower-alkyl, monocarbocyclic aryl, monocarbocyclic aryl-lower-alkyl or monocarbocyclic aryl-lower-alkenyl radical. When R R or R represents a loWer-alkyl radical, it can be straight or branched and can contain from one to about six carbon atoms. R R and R thus stated, inter alia, for methyl, isopropyl, isobutyl or n-heXyl.

When R represents an hydroxy-lower-alkyl radical, it can be straight or branched, can contain from two to about six carbon atoms and is such that the oxygen and nitrogen atoms are separated by at least two carbon atoms. R thus also stands, inter alia, for 2-hydroxyethyl, 3-hydroXy-l-methylpropyl or 6-hydroxyhexyl.

When R R or R represents a monocarbocyclic aryl radical, or when R or R represents a monocarbocyclic aryl-lower-alkyl or a monocarbocyclic aryl-lower-alkenyl $9 radical or when R represents a bis(monocarbocyclic aryl)-lower-alkyl radical, each lower-alkyl and loweralkenyl moiety of said radicals can contain up to about four carbon atoms and each monocarbocyclic aryl moiety of said radicals can be further substituted as will be hereinafter described and each monocarbocyclic aryl moiety, to-

ether withsaid substituents, can contain from six to about twelve carbon atoms. The monocarbocyclic aryl moiety can thus be phenyl or phenyl substituted by one or more substituents selected from the group consisting of halogen (including fluorine, chlorine, bromine and iodine), loweralkyl, hydroxy, lower-alkoxy, methylenedioxy, ethylenedioxy, lower-alkylmercapto, lower-alkylsulfinyl, loweralkylsulfonyl and trifluoromethyl. When the monocarbocyclic aryl moiety is substituted by more than one of the above substituents, the substituents can be the same or different and can occupy any of the available positions on the phenyl ring. When the substituent is a lower-alkyl, lower-alkoXy, lower-alkyhnercapto, lower-alkylsulfinyl or lower-alkylsulfonyl group, said substituents can be either straight or branched and can contain from one to about four carbon atoms. Thus when R R or R represents a monocarbocyclic aryl, monocarbocyclic aryl-lower-alkyl, bis(monocarbocyclic aryl)-lower-alkyl or a monocarbocyclic aryl-lower-alkenyl radical, each of R R and R; can represent such organic radicals, inter alia, as phenyl, benzyl, phenethyl, 4-phenylbutyl, benzhydryl or cinnamyl or such organic radicals substituted in the phenyl ring by one or more of such substituents, inter alia, as fluoro, chloro, bromo, iodo, methyl, isobutyl, hydroxy, methoxy, n-butoxy, methylenedioxy, ethylenedioxy, methylmercapto, isopropylmercapto, methylsulfinyl, isopropylsulfinyl, methylsulfonyl, isopropylsulfonyl or trifiuoromethyl.

In the above general Formulae la, b and 0 when R represents a heteromonocyclic radical, it can represent a heteromonocyclic radical containing one or more heteroatorns such as nitrogen, oxygen or sulfur. Thus R also stands, inter alia, for pyrimidyl, pyrazinyl, pyridyl, thiazolyl, oxazolyl, 1,3,5-triazinyl, thienyl, and the like.

In the above general Formulae Ia, b and 0, R and R represent hydrogen atoms or each of R and R can represent a loWer-alkyl radical or one of R and R can represent a lower-alkyl radical while the other of R and R represents a hydrogen atom. When R and R represent lower-alkyl radicals, they can contain from one to about three carbon atoms, can be straight or branched and can occupy either the 2-, 3-, 5- or 6-position of the piperazine ring or the 2-, 3-, 5-, 6- or 7-positions of the homopiperazine ring. R and R thus stand for hydrogen, methyl, ethyl, n-propyl or isopropyl.

In the above general Formulae la, b and c, n represents an integer from one to seven and, in Formula Ia when X is a hydroxyl radical, must be at'least two. The loweralkylene group, C H can be straight or branched and stands, inter alia, for methylene, ethylene, propylene, butylene, Z-methylpropylene, Z-methylbutylene, 2-ethylbutylene, 2-ethy1pentylene and the like.

The compounds of Formulae la, b and c can be prepared by the following reactions in which R R R R R R X, n and m have the meanings given above, except that R does not represent a hydrogen atom and Hal represents a halogen atom and Alk represents a loweralkyl radical. The compounds of Formulae la, b and c where R represents a hydrogen atom are prepared in a manner as will be hereinafter described.

N u Ru 5 (VII a, b, 0)

Method E:

R CHzO HN N-Rg Ia (n is 1) Twat).

Method A above can be used to prepare 1-[(1-, 2- and 7 5 3-1ndolyl)-loWer-alky1] -4-substituted-piperazines and 1- [(l-, 2- and 3-indolyl)-lower-alkyl]-4-substituted-hom0 piperazines of Formulae la, b or c where X in Formula la is a hydrogen atom. T' e intermediate indolyl-loweralkyl halides of Formula Ila, b or 0, used as starting materials in Method A above, are prepared by reduction of an indolyl 2- or 3-carboxylic acid or an indole 1-, 2-, or 3-alkanoic acid with lithium aluminum hydride and conversion of the resulting alcohol to the corresponding halide by reacting the former with, for example, a phosphorus trihalide or a thionyl halide. The (l-, 2- and 3-indolyl)-lower-alkyl halides thus produced are reacted with an appropriate l-substituted-piperazine or l-substituted-homopiperazine at a temperature between about 50 C. and 150 C. in the presence of an acid-acceptor. The reaction is preferably carried out in an organic solvent, inert under the conditions of the reaction, such as anhydrous ethanol, benzene, xylene and the like. The purpose of the acid-acceptor is to take up the hydrogen halide which is split out during the course of the reaction. The acid-acceptor is a basic substance which forms water soluble by-products easily separable from the main product of the reaction and includes such substances as alkali metal salt of weak acids, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, sodium alkoxides, and the like. The acid-acceptor can also be in the form of an excess quantity of the l-substituted-piperazine or l-substituted-homopiperazine.

The compounds of Formula Ia where X is H and n is at least 2 can also be prepared by reacting an indole with a 1-(w-hydroxy-loWer-alkyl)-4-substituted piperazine or a 1- w-hydroxy-lower-alkyl -4-substituted-homopip eraziue in the presence of a Raney nickel catalyst. The reaction is preferably carried out in an organic solvent inert under the conditions of the reaction, such as xylene, cymene or di-n-butyl ether, and the like.

Method B above can be used to prepare l-[2-(3-ir1- dolyl) ethyl]-4-substituted-piperazines, l-[2-(3-indolyl) ethyl]-4-substituted-homopiperazines, l-[2-(3-indolyl)-2- hydroxyethyl]-4-substituted-piperazines and 1-[2-(3-indolyl)-2-hydroxyethyl] 4 substituted-homopiperazines, i.e. compounds of Formula Ia where n is 2 and X is a hydrogen atom or a hydroxyl radical. The intermediate indoles used as starting materials in Method B above are prepared by known methods, for example by the Fischer indole synthesis using an appropriate substituted phenylhydrazine and a methyl lower-alkyl ketone or a methyl monocarbocyclic aryl ketone. Alternatively the starting indoles can be prepared by catalytic reduction of a [3,2- dinitrostyrene. The indoles thus prepared are reacted with a glyoxalyl halide at a temperature in the range from about C. to C. in an organic solvent inert under the conditions of the reaction, such as ether, petroleum ether, dioxane, tetrahydrofuran and the like, thus affording the 3-(indolyl)-glyoxalyl halides or Formula Illa. A preferred solvent is ether. The 3-(indolyl)glyoxalyl halides of Formula Illa thus prepared are then reacted with a l-substituted-piperazine or a l-substitutedhomopiperazine at a temperature between about 5 C. and about 65 C. in the presence of an acid-acceptor to give the 1-[(3-indolyl)-glyoxalyl] 4 substituted-piperazines and l- (3-indolyl glyoxalyl] -4-substituted-hornopiperazines of Formula Fla. The reaction is preferably carried out in an organic solvent, inert under the conditions of the reaction, such as tetrahydrofuran, ether, ethylene dichloride and the like. The purpose of the acidacceptor is to take up the hydrogen halide which is split out during the course of the reaction. The acid-acceptor is a basic substance which forms water-soluble by-products easily separable from the main product of the reaction and includes such substances as alkali metal salts of weak acids, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, and the like. The acid-acceptor can also be in the form of an excess quantity of the l-substituted-piperazine or l-substituted-homopiperazine. A preferred solvent is tetrahydrofuran and it is preferred to use an excess quantity of the l-substitutedpiperazine or 1-substituted-homopiperazine as the acidacceptor. The l- 3-ind0lyl glyoxalyl] -4-substituted-piperazines and l-[(3-indolyl)glyoxalyl]-4-substituted-homo-piperazines thus prepared are reacted with an alkali metal aluminum hydride at a temperature between about 0 C. and about C. in an organic solvent inert under the conditions of the reaction, for example, ether or tetrahydrofuran. It is preferred to use lithium aluminum hydride in refluxing tetrahydrofuran.

Method B affords compounds of Formula I where the piperazinyl-lower-alkyl, hornopiperazinyl-lower-alkyl, piperaZinyl-w-hydroxy-lower-alkyl or homopiperazinyl-whydroxy-lower-alkyl group is attached to the 3-posiiton of the indole nucleus. When R in compounds of Formula IV a is a hydrogen atom, the main product is a 1-[2-(3-indolyl)ethyl]-4-substituted-piperazine or a l-[2-(3-indolyl)ethyl]-4-substituted-homopiperazine, i.e., Ia, wherein X is H and n is 2, although it is possible to obtain both l-[2-(3-indolyl) 2 hydroxyethyl]-4-substituted-piperazines or 1-[2-(3-indolyl)-2-hydroxyethyl]-4-substitutedhomopiperazines and l-[2-(3-indolyl)ethyl]-4-substituted piperazines or l-[2-(3-indolyl)ethyl]-4-substituted-homopiperazines. However, when R in compounds of Formula PM is a lower-alkyl, monocarbocyclic aryl, monocarbocyclic aryl-lower-alkyl or a monocarbocyclic aryllower-alkenyl radical, the only products obtained on reduction with an a kali metal aluminum hydride are the corresponding 1- 2- 3-indolyl -2-hydroxyethylj -4-substituted-piperazines and 1-[2-(3-indolyl)-2-hydroxyethyl]- r-substituted-homopiperazines, i.e., Ia, X is OH. It is nevertheless possible to obtain l-[w-(3-indolyD-w-hydroXy-lower-alkyl]-4-substituited-piperazines and 1-[w-(3- indolyl)-w-hydroXy-lower-alkyl] 4 substituted-homopiperazines of Formula la wherein R is H by another method as will be hereinafter described.

Method C can also be used to prepare compounds of general Formula Ia where the piperazinyl-w-hydroxy-' lower-alkyl group, homopiperazinyl-w-hydroxy-loWer-alkyl group, piperazinyl-lower-alkyl group or the homopiperazinyl-lower-alkyl group is attached to the 3-position of the indole nucleus. The starting indole Grignard reagent is prepared by reacting an indole having no substituent in the l-position of the indole nucleus with a loweralkyl magnesium halide in an appropriate organic solvent, for example ether or tetrahydrofuran, and reacting the resulting indolemagnesium halide with a 4-substituted-piperaZinyl-lower-alkanoyl halide or a 4-subsstituted-l-homopiperazinyl-lower-alkanoyl halide to give the 1-[w-(3- indolyl)-w-keto-lower-alkyl]-4-substituted-piperazines and l-[o-(3-indolyl)-w-keto-lower-alkyl] 4 substituted-ho mopiperazhles of Formula Va. The latter on reaction with an alkali metal aluminum hydride as described above, preferably lithium aluminum hydride, afiord 1-[w-(3-indolyl)-loWer-alkyl]-4-substituted-piperazjnes and l-[w-(3-ii1- dolyl)-lower-alkyl]-4-substituted-homopiperazines of Formula Ia where X and R are hydrogen atoms. However, on reaction of the l-[w-(3-indoly1)-w-keto-lower-alkyl]-4- substituted-piperazines or the l-[w-(3-indolyl)-w-ketolower-alkyl]-4-substituted-homo-piperazines of Formula Va with an alkali metal borohydride, 1-[w-(3-indolyl)-whydroxy-lower-alkyl]-4-substituted-piperazines and l-[w- (3 indolyl) w hydroxy-lower-alkyl] 4 substituted-homo-piperazines can be obtained, i.e., Ia, X is OH, R is H. The reaction is preferably carried out in an organic solvent inert under the conditions of the reaction, for example methanol, ethanol, ether, tetrahydrofuran and the like. A ternatively, the compounds of Formula Va can be reacted With a lower-alkyl halide, a monocarbocyclic aryllower-alkyl halide or a monocarbocyclic aryl-lower-alkenyl halide in the presence of an acid-acceptor to give the 1-[w-(3-indolyl)-u-keto-lower-alkyl] 4 substitutedpiperazines and the l-[w-(3-indolyl)-w-keto-lower-alkyl]- 4-substituted-homopiperazines of Formula VIa where R; is not a hydrogen atom. The purpose of the acid-acceptor is to take up the hydrogen halide which is split out during the course of the reaction. The reaction is preferably carried out in liquid ammonia in the presence of an alkali metal amide, for example, sodium amide. The compounds of Formula VIa thus prepared can then be reacted with an alkali metal aluminum hydride or an alkali metal borohydride as described above, preferably lithium aluminum hydride or sodium borohydride, to give 1-[w- (3-indolyl)-w-hydroxy-lower-alkyl] 4 substituted piperazines and l- [w- (3-indolyl) -w-hydroxy-lower-alkyl] -4-substituted-hornopiperazines of Formula Ia where X is CH. Method D above can be used to prepare 1-[(1-, 2- and 3-indolyl)-lower-alkyl] 4 substituted-piperazines and 1-[(l-, 2- and S-indolyl)-lower-alkyl]-4-substituted-homopiperazines of Formula la, b or c Where X is H and n is an integer from one to seven. The intermediate mixed anhydrides used as starting material are prepared by re acting a 1, 2- or B-indolyl-lower-alkanoic acid or a 2- or 3-indolecarboxylic acid with a lower-alkyl-haloforrnate in the presence of an acid-acceptor, for example triethylamine, at a temperature between about -20 C. to about 20 C. The reaction is preferably carried out in an organic solvent inert under the conditions of the reaction such as anhydrous acetone, ether, ethylene dichloride and the like. Acetone is the preferred solvent. The purpose of the acid-acceptor is to take up the hydrogen halide split out during the course of the reaction and is a basic substance which forms water-soluble by-products easily separable from the product. The indolyl-lower-alkane mixed anhydrides of the 1-, 2- and 3-indole-l0Wer-alkanoic acids, and the 2-indolecarboxylic acids and S-indolecarboxylic acids thus formed in situ are reacted with an appropriate l-substituted-piperazine or l-substitutedhomopiperazine at a temperature between about 20 C. and about 20 C. to give the 1-[(l-, 2- and 3-indolyl)-uketo-lower-alkyl]-4-substituted-piperazines, 1-[(1-, 2- and 3-indolyl)-a-keto-lower-alkyl] 4 -substituted-homopiperazines, 1-(2-indolylcarbonyl)-4-substituted-piperazines, 1-(2-indolylcarbonyl)-4-substituted homopiperazines, 1- ('3-indolylcarbonyl)-4-substituted-piperazines and the 1- (3-indolylcarbonyl) 4 substituted-homopiperazines of Formula VIIa, b and c. The latter on reaction with an alkali metal aluminum hydride as described above, preferably lithium aluminum hydride, afford compounds of Formulae la, b or wherein X is H and n is an integer from one to seven.

Alternatively the l-[(3-indolyl)-a-keto-lower-alkyl]-4- substituted-piperazines and l-[(S-indolyl)-u-keto-loweralkyl]-4-substituted-homopiperazines of Formula Vila where R; is hydrogen can be prepared by reacting an indole having no substituent in the 1-position of the indole nucleus with a lower-alkyl magnesium halide in an appropriate organic solvent, for example ether or tetrahydrofuran, and reacting the resulting indole magnesium halide with a l-(halo-lower-alkanoyl)-4-substituted-piperazine or a 1 (halodower-alkanoyl)-4-substituted-homopiperazine thus producing the compounds of Formula VIIa where R.;, is hydrogen and n is an integer from two to seven.

Method B above can be used to prepare l-[(3-indolyl)- methyl] 4 substituted-piperazines and 1-[(3-indolyl) methyl]-4-substituted-homopiperazines, that is, compounds of Formula Ia where X is H and n is 1. The 1- 3-indolyl) methyl] 4-substituted-piperazines and 1- (3- indolyl)methyl]-4-substituted-homopiperazines are prepared by reacting an indole with formaldehyde and an appropriate l-substituted-piperazine or l-substituted-homopiperazine at a temperature between about 50 C. and about 150 C. The formaldehyde can be in the form of an aqueous solution, i.e. 40% formalin solution, or a polymeric form of formaldehyde such as paraformaldehyde or trioxymethylene. When such polymeric forms are used, a molar excess of mineral acid such as hydrochloric acid, is added to regenerate the free aldehyde from the polymer. The reaction is preferably carried out in an organic solvent, inert under the conditions of the reaction, such as ethanol, methanol or 3-methylbutanol.

The compounds of Formulae Ia, b or c where R is a hydrogen atom are prepared by reacting with hydrogen in the presence of a catalyst the 1-[(1-, 2- and 3-indolyl)- lower-alkyllpiperazines, 1-[(1-, 2- and 3-indolyl)-loweralkyHhomopiperazines, 1-[w-(3-indolyl)-w-hydroxy-loweralkyl]piperazines or 1-[w-(3-indolyl)-w-hydroxy-loweralkyljhomopiperazines of Formulae Ia, b or c in which the piperazine or homopiperazine ring bears attached to the 4-position a benzyl, benzhydryl or cinnamyl radical. The reaction is preferably carried out in the presence of a' platinum or palladium catalyst in an organic solvent inert under the conditions of the reaction, for example ethanol,

cellosolve, benzene, toluene and the like and at hydrogen pressures in the range from about 30 psi. to about p.s.i. The benzyl, benzhydryl or cinnamyl radicals can be unsubstituted or substituted in the phenyl ring by substituents of the nature described above but which do not take part in or adversely affect the reaction thus excluding such substituents as those containing sulfur, for example loweralkyl-mercapto, or halogen. A preferred catalyst is palladium-on-charcoal and a preferred solvent is ethanol.

In the procedures described above, the piperazine or homopiperazine moiety is attached as a complete ring to the indolyl moiety either through a lower-alkyl or loweralkanoyl chain. The compounds of Formulae Ia, b or 0 above can also be prepared using the same general procedures as described above except that the piperazine or homopiperazine ring is closed after an N-benzyl-N-substituted-lower-alkylenediamine group has been joined to the indolyl moiety through a lower-alkylene or a lower-alkanoyl chain. The procedure is particularly adaptable to the preparation of compounds of Formulae Ia, b or 0 wherein R and/ or R represent lower-alkyl radicals. The procedure is illustrated below using Method D, but it is to be understood that the other methods described above can be used as well. In the following reactions R R R R R R n, m and Hal have the meanings given above.

(IXa, b, c)

In the above procedure an N-benzyl-N-substitutedlower-alkylene diamine is reacted, in the above instance, with a mixed anhydride of a 1-, 2- or 3-indole-loweralkanoic acid or a 2- or 3-indolecarboxylic acid using the same conditions as described above in the description of Method D for the reaction of an indolyl-lower-alkane mixed anhydride with a l-substituted-piperazine or a 1- substituted-homopiperazine thus producing the compounds of Formulae VIIla, b or c. The lower-alkylene radical, which is an ethylene radical when m is l or a propylene radical when m is 2, can be further substituted by a straight or branched lower-alkyl radical, R and the loWer-alkyl radical can occupy any of the carbon atoms of the ethylene or propylene radical, although for the purpose of i lustration only it is shown above in Formulae Villa, b and c on the carbon atom adjacent to the amide nitrogen atom. Compounds of Formulae Vllla, b and wherein R is attached to the carbon atom adjacent to the amide nitrogen atom afford compounds of Formulae la, b and c wherein the loWer-alkyl radical is attached to the 2-position of the piperazine ring or the 7-position of the homopiperazine ring. Compounds of Formulae la, b and 0 wherein the lower-alkyl radical is attached to the 3-position of the piperazine ring or the 5-position of the homopiperazine ring can be prepared using an N-benzyl-N-substituted-lower-alkylenediamine bearing a loWer-alkyl radical on the carbon atom adjacent to the tertiary-amino group or by another alternative procedure as will be hereinafter described, and compounds of the Formulae la, b and 0 wherein the lower-alkyl radical is attached to the 6-position of the honiopiperazine ring can be prepared using an N-benzyl-N-substitutedpropylenediamine bearing a loWer-alkyl radical on the 2- position of the propylene radical.

The compounds of Formulae Villa, 1) and c thus prepared are reacted with an alkali metal aluminum hydride, using the same conditions as described above in the description of Methods B, C and D for the reaction of compounds of Formulae IVa, Va, V112, and Vila, b and c with an alkali metal aluminum hydride, thus producing the corresponding N-(1-, 2- and 3-indolyl-lower-alkyl)- N-benzyl-N'-substituted-lower-alkylenediamines of Formulae IXa, b and c. It is preferred to use lithium aluminum hydride. It will be appreciated that Methods A, B, C and E can be adapted to the above-described synthesis as well and further that Methods B and C afford N- [w-(3-indolyl)-w-l1ydr0xy-lower-alkyl]-N' benzyl-N'-substituted-lower-alkylenediamines corresponding to the compounds of Formulae IXa, b and c. That is, it is only necessary to substitute for the l-substituted-piperazine and the l-su'ostituted-homopiperazine used in Methods A, B and E the corresponding N-benzyl-N-substituted-ethylenediamine and N-benzyl-N-substituted-propylenediamine,

respectively, or to substitute for the 4-substituted-1- piperazinyl-lower-alkanoyl halide and the 4-substituted-lhomopiperazinyl-loWer-alkanoyl halide used in Method C the corresponding N-(N-benzyl-N-substituted-ethylenediamino)-lower-alkanoyl halide and N-(N'-benzyl-N-substituted-propylenediamino)-lower-alkanoyl halide, respectively, and proceed as will be hereinafter described. It will also be appreciated that the latter step involving reaction of the intermediate amide with an alkali metal aluminum hydride can be omitted when using Methods A, C and E. it is only necessary to convert the amide produced in Methods B and D to the corresponding secondary amine before proceeding to the next step.

The N-(l-, 2- and 3-indolyl-lower-alkyl)-N'-benzyl- N'-substituted lower alkylenediamines corresponding to Formulae IXa, b, and c and the N-[w-(3-indolyl)-w-hydroXy-loWer-alkyl]-N'-benzyl N substituted lower-alkylenediamines corresponding to Formula IXa, thus produced are then reacted with an zxor fi-halo-lower-alkanoyl halide at a temperature between about 0 C. and 90 C. to give the benzohalide quaternary ammonium salts of the 1-[(l-, 2- and 3-indolyl)-lower-alkyl]-4-substituted-Z-piperazinones, l-[(l-, 2- and 3-indolyl)-loweralkyl1-4-substituted 2 homopiperazinones, 1-[w-(3-indolyl)-w-hydroxy-loWer-alltyl] 4 substituted 2 piperazinones and I-[w-(B-indolyl)-w-hydroXy-lower-alkyl]-4- substituted-2-homopiperazinones corresponding to Formulae Xa, b and c. The reaction can be carried out either with or without the use f an acid-acceptor and is preferably conducted in an organic solvent inert under the conditions of the reaction, for example, methylene dichloride, chloroform, ethylene dichloride, benzene and the like. For the purpose of illustration only, an a-haloloWer-alkanoyl halide is shown in the above-described reaction. However, an alternative procedure for preparing the benzohalide quaternary ammonium salts of the l-[(l-, 2- and 3-indolyl)-loWer-alkyl] 4 substituted-2- homopiperazinones and the 1-[w-(3-indolyl)-w-hydroxylower-alltyl]-4-substituted 2 homopiperazinones corresponding to Formulae Xa, b and c comprises reacting an N-(1-, 2- or 3-indolyl-loWer-alkyl)-N'-benzyl-N'-substituted-ethylenediamine corresponding to Formulae IXa, b and c (m is 1) or an N-[w-(3-indolyl)-w-hydroxy-lower-alkyl]-N-benzyl-N'substituted-ethylenediamine corresponding to Formula Lia (m is l) with a B-halo-loweralkanoyl halide using conditions similar to those described above when an et-halo-lower-alkanoyl halide is used. The uor B-halo-lower-alkanoyl halides can be straight or branched and the B-halo-lower-alkanoyl halide can contain lower-alkyl radicals, R or R on either the ocor the B-carbon atom. Thus compounds of Formulae Xa, b and c can be obtained wherein R and R can occupy the 3-, 5- or 6-positions of the Z-piperazinone ring, or the 3-, 5-, 6-, or 7-positions of the 2-homopiperazinone ring or the 2-, 3-, 5- or o-positions of the 7-homopiperazinone ring, and by proper choice of the N-benzyl-N-substituted-lower-alkylenediamine, or the aor B-halo-loweralkanoyl halide, compounds of the invention can be obtained where R and/ or R represent such groups, inter alia, as methyl, ethyl, propyl or isopropyl.

The benzohalide quaternary ammonium salts of the 1- [(l-, 2- and 3-indolyl)-lower-alkyl]-4-substituted-2-piperazinones, l-[(1-, 2- and 3-indolyl)-lower-alkyl]-4-substituted-2- and 7-homopiperazinones, l-[w-(3-indolyl)-whydroxy-lower-alkyl]-4-substituted-2- iperazinones and l- [w-(3-indolyl)-w-hydroxy-lower-alkyl1 4 substituted-2- and 7-homopiperazinones corresponoding to Formulae Xa, b and c are then catalytically debenzylated to the corresponding free bases of Formulae Xla, b and c by reacting the former With hydrogen in the presence of a catalyst at a temperature from about 20 C. to about C. and under hydrogen pressures in the range from about 30 psi. to about 70 psi. The reaction is conducted in an organic solvent inert under the conditions of the reaction, for example methanol, ethanol or 2- propanol. A preferred catalyst is palladium-on-charcoal and a preferred solvent is ethanol.

It will be appreciated that, when R represents a benzyl, benzhydryl or cinnamyl radical in the compounds of Formulae Xa, b and c, this radical can also be removed by catalytic debenzylation to give compounds of Formulae Xla, b and c where R is hydrogen. This synthetic method therefore provides a second process for preparing compounds of Formulae la, b and c where R is hydrogen.

The l-[(l-, 2- and 3-indolyl)lower-alkyl] -2-pipera zinones, l-[( 1-, 2- and 3-indolyl)-lower-alkyl]-2- and 7- homopiperazinones, 1-[w-(3-indolyl)-w-hydroxy loweralkyl]-2-piperazinones and l-[w-(3-indolyl)-w-hydroxylower-alkylJ-Z- and 7-homopiperazinones corresponding to Formulae XIa, b and c are then reacted with an alkali metal aluminum hydride, preferably lithium aluminum hydride, using conditions previously described, to give compounds of Formulae la, b and wherein R and/or R is either a hydrogen atom or a lower-alkyl radical.

Another synthetic procedure which provides access to compounds of Formulae Ia, b and 0 wherein R and/ or R is hydrogen or a lower-alkyl radical is illustrated be low by the following reactions wherein R R R R R R 11, m and Hal have the meanings given above except that R does not represent hydrogen:

An N-(fior -halo-lower-alkyl)-N,N-dibenzylamine is reacted with a primary amine, R NH at a temperature between about 50 C. and about 150 C. in the presence of an acid-acceptor. The reaction is preferably carried out in an organic solvent, inert under the conditions of the reaction, such as anhydrous ethanol, benzene, xylene, 2- ethoxyethanol (Cellosolve), and the like. The nature of the acid-acceptor is the same as that described above in the preparation of l-[(l-, 2- and 3-indolyl)-lower-alkyl]- 4-substituted-piperazines and 1-[(1-, 2- and 3-indolyl)- loWer-alkyl]-4-substituted-homopiperazines using Method A. The lower-alkyl radical, which is an ethylene radical when m is 1 or a propylene radical when m is 2, can be further substituted by a straight or branched lower-alkyl radical, R and the lower-alkyl radical, R can occupy any of the carbon atoms of the ethylene or propylene radical, although for the purpose of illustration only it is shown above on the carbon atom adjacent to the tertiary amino group. The compounds of Formula XII thus produced wherein R is attached to the carbon atom adjacent to the tertiary amino group afford compounds of Formula la, b or 0 wherein the lower-alkyl radical, R is attached to the 2-position of the piperazine ring or the 7-position of the homopiperazine ring. Compounds of Formulae la, b or 0 wherein the lower-alkyl radical is attached to the 3-position of the piperazine ring or the 6- position of the homopiperazine ring are obtained from compounds of Formula XII where R is attached to the B-carbon atom of the ethylene or propylene radical, respectively, and the compounds of Formulae Ia, b or'c where the lower-alkyl radical, R is attached to the 5- position of the homopiperazine ring are obtained from compounds of Formula XII where the lower-alkyl radical, R is attached to the -y-carbon atom of the propylene radical (i.e. m is 2). The homopiperazines can also be prepared by another method as will be hereinafter described.

The 1-(N,N-dibenzylamino)-2- or 3-(N'-substituted)- lower-alkylene-secondary amines of Formula X11 thus produced are reacted with an aor B-halo-lower-alkanoyl halide using conditions similar to those described above in the description of the preparation of compounds of Formula X. The uor S-halo-lower-alkanoyl halide can be any 01- or ;8-halo-lower-alkanoyl halide or the type described above in the description of the preparation of compounds of Formula Xa, b and c.

The resulting l-(N,N-dibenzylarnino)-2-[N'-(aor '5- halo-lower-alkanoyl)-N'-(substituted)] lower alkylenediarnines of Formula XIII can be isolated and purified or if desired quaternized in the crude form by refluxing in an appropriate organic solvent inert under the conditions of the reaction, for example ethanol, acetonitrile or Cellosolve. A preferred solvent is Cellosolve.

For the purpose of illustration only, an a-halo-loweralkanoyl halide is shown in the above-described reaction. However, by reacting a fi-halo-loWer-alkanoyl halide with ethylenediamine derivatives of Formula XII, the 1- benzyl-4-substituted-5-hornopiperazinones corresponding to Formula XIV can be obtained. The uor fi-halo-lo-wer-alkanoyl halides can be straight or branched and the fi-halo-lower-alkanoyl halide can contain lower-alkyl radicals, R or R on either the 126- or the B-carbon atom. Thus, by proper choice of the 04- or B-halo-lower-alkanoyl halide, compounds of Formula XIV afford, as will be seen, compounds of Formulae Ia, b or c where a loweralkyl radical,,R is attached to the 2-position of the piperazine ring or to the 6- or 7-positions of the homopiperazine ring.

The 1-benzyl-4-substituted-3-piperazinone and l-benzyl- 4-substituted-S-homopiperazinone benzohalide quaternary ammonium salts of Formula XIV thus produced are catalyticall-y debenzylated to the l-substituted-2-piperazinones and 1-substituted-7-homopiperazinones of Formula XV using the same conditions as described above in the description of the preparation of compounds of Formula XIa, b and c. The l-substituted-2-piperazinones and 1- substituted-7-hornopiperazinones of Formula XV can be isolated and purified in the form of the free base or if desired can be converted to an acid-addition salt for purposes of purification and characterization. Appropriate acid-addition salts are those derived from mineral acids as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid and phosphoric acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid and p-toluenesulfonic acid. 1

The 1-substituted-2-piperazinones and l-substituted-7-' homopiperazinones thus produced can then be reacted,

for example, with a (1-, 2- or 3-indolyl)-lower-al-kyl halide according to the procedure of Method A above and the resulting l-[(l-, 2- and 3-indolyl)-lower-alkyl] -4-substituted-3-piperazinone or l-[(l-, 2- and 3-indolyl)-loweralkyl]-4-substituted-5-homopiperazinone reacted with an alkali metal aluminum hydride to produce the 1-[(l-, 2- or 3-indolyl)-lower-alkyl]-4-substituted-piperazines or 1- [(1-, 2- or 3-indolyl)-lo .ver-alkyl]-4-substituted-homopiperazines of Formulae la, b and c.

Method A was chosen above for purposes of illustration only but it is to be understood that Methods B, C, D and E can be adapted to the above-described synthesis as well. That is, it is only necessary to substitute for the l-substituted-piperazine and the l-substituted-homopiperazine used in Methods A, B, D and E. or the 4-substituted-lpiperazinyl-lower-alkanoyl halide and 4-substituted-l-homopiperazinyl-lower-alkanoyl halide used in Method C the corresponding l-substituted-Z-piperazinones and l-substituted-7-homopiperazinones or the l-(4-substituted-3-piperazinonyl)-lower-alkanoyl halide and 1-(4- substituted-S-homopiperazinonyl)-lower-alkanoyl halide, respectively, and proceed as described above. Thus in addition to the 1-[(l-, 2- and S-indolyl)-lower-alkyl]-4- substituted-3-piperazinones and l-[(l-, 2- and 3-indolyl)- lower-alkyl]-4-substituted-5-homopiperazinones afiorded by Method A, there can also be obtained 1-[(3-indolyl) glyoxalyl]-4-substituted-3-piperazinones and l-[(3-indolyl)glyoxalyl]-4-substituted 5 homopiperazinones by Method B, l-[w-(3-indolyl)-w-keto-lower-all yl]-4-substituted-3-piperazinones and 1-[w-(3-indolyl)-w-keto-loweralkyl]-4-substituted-5-homopiperazinones by Method C, 1-[(l-, 2- or 3-indolyl)-a-l eto-lower-allyl]-4-substituted- 3-piperazinones and l-[(l, 2- or 3-indolyl)-u-keto-loweralkyl]-4-substituted-S-homopiperazinones by Method D and 1-[ (3-indolyl) methyl] -4-substituted-3-piperazinones, 1[(3-indolyl)methyl] 4 substituted-5-homopiperazinones by Method B. These on reaction with an alkali metal aluminum hydride afford, as the case may be, either the l[(1-, 2- and 3-indolyl)-lower-alkyl]-4-substitutedpiperazines, 1[(l-, 2- and 3-indolyl)-lower-alkyl]-4-substituted homopiperazines, 1-[w-(S-indolyl)-w-hydroxylower-alkyl] -4-substituted-piperazines or the l-[w-(S-indolyl) w-hydroxy-lower-alkyl]-4 substituted-homopiperazines of Formulae la, b and c.

An alternative procedure for the preparation of the l substituted-7-homopiperazinones of Formula XV that are obtained when a B-halo-lower-alkanoyl halide is reacted with an ethylene-diamine of Formula Xll (m is 1) comprises reacting a 1-substituted-4-piperidone with hydrazoic acid in the presence of a strong mineral acid, for example sulfuric acid, phosphoric acid or hydrochloric acid, and in an appropriate organic solvent inert under the conditions of the reaction, for example benzene, chloroform, trichloroethylene and the like. The hydrazcic acid can be in the form of a solution of hydrazoic acid in the solvent used or, if desired, in the form of an alkali metal salt, for example sodium azide. In the latter case, the alkali metal salt reacts with the mineral acid used to produce the hydrazoic acid in situ. The reaction is preferably carried out at a temperature in the range from about l C. to 25 C. Preferred solvents are benzene and chloroform and a preferred acid is sulfuric acid.

The method is particularly preferred for the preparation of 1-substituted-homopiperazines corresponding to Formula XV where R and R are both hydrogen atoms. However, l-substituted-homopiperazinones where R and R are both the same lower-alkyl radical are also prepared advantageously by this method from symmetrical 1-substituted-di-lower-alkyli-piperidones, such as l-substituted-Z,6-di-lower-alkyl-4-piperidones or l-substituted- 3,5-di-lower-alkyl-4-piperidones, since the racemic mixture of 1-substituted-di-lower-alkyl-S-hOmopiperaZinones produced in the reaction give, on reduction with an alkali metal aluminum hydride, a racemic mixture of the same l-substituted di loweral-kyl-homopiperazine. On the other hand, when l-substituted mono-lower-alkyll-piperidones or unsymmetrical l-substituted-di-lower-alkyl-4- piperidones are employed, for example a l-substituted- 2,5-di-lower-alkyll-piperidone, the mixture of products, on reduction with an alkali metal aluminum hydride, give isomeric l-substituted-homopiperazines and thus necessitate a separation of the isomers before proceeding to the next step.

Pharmacological evaluation of the compounds of Formulae la, b and c has demonstrated that they possess a variety of depressant actions on the central and autonomic nervous system, the cardiovascular system and the skeletal-muscular system. They lower the blood pressure; they decrease the incidence of vomiting induced by apomorphine; they lower the rectal temperature; they potentiate the sleeping time induced by ether, thiopental sodium or hexobarbital sodium; and they produce tranquilization and skeletal muscle relaxation. These results indicate their usefulness as hypotensive agents, antinauseants, antipyretics, sedatives, tranquilizers and skeletal muscle relaxants. The compounds can be prepared for use by dissolving under sterile conditions a salt form of the compounds in water (or an equivalent amount of a nontoxic acid if the free base is used), or in a physiologicaLly compatible aqueous medium such as saline, and stored in ampules for intramuscular injection. Alternatively, they can be incorporated in tablet or capsule form for oral administration. They are formulated and used in the same way as known compounds having similar activities, such as chlorpromazine. The toxicity of the compounds of the invention is of the same order of magnitude as that of chlorpromazine.

The structures of the compounds of the invention have been established by the mode of synthesis and corroborated by chemical analysis.

The following example will further illustrate the invention without the latter being limited thereto.

PREPARATION OF INTERMEDIATES Example 1.-1-[2-(3-Indolyl)Ethyl]-4-Methyl-2- Piperazinone Benzochloride [Xag R1, R3, R4, R5 and R5 are H, R2 is CH3, C I-1 iS CH CH m iS 1, Hal is Cl A solution of 11.5 g. (0.07 mole) of N-benzyl-N-methylaminoethylamine in 20 ml. of tetrahydrofurau was added over a five minute period with stirring to a solution of 14.6 g. (0.07 mole) of 3-indoleglyoxalyl chloride in ml. of tetrahydrofuran. The mixture, which had become quite warm, was allowed to stand for about a half hour. About one liter of water and one equivalent of aqueous sodium hydroxide were added, and the product which separated was collected and recrystallized twice from ethanol giving 9.7 g. of N-benzyl-N'-(3-indolyl)- glyoxalyl-N-methylethylenediamine, Ml. l24.5-l27 C. (uncorn). [corresponds to Villa; R R R and R are E, R2 is CH3, m 1, and C 1H2 2 is Twenty-six grams (0.078 mole) of the N-benzyl-N'- (3-indolyl)glyoxalyl-N m thylethylenediamine dissolved in ml. of tetrahydrofuran were added to a stirred suspension of 19 g. (0.05 mole) of lithium aluminum hydride in 250 ml. of tetrahydrofuran. The greenish mixture was refluxed and stirred for seven hours and then allowed to stand overnight at room temperature. A solution of 25 ml. of water and 75 ml. of tetrahydrofuran was added with stirring over a period of two and a half hours. An additional 30 ml. of water was added, the mixture was stirred for one hour, and 250 ml. of methylene dichloride was added and stirring continued for another half hour. The reaction mixture was filtered, the filter was washed with methylene dichloride, and the filtrate dried over magnesium sulfate and taken to dryness giving a light brown oil. The oil was crystallized from ethyl acetate giving 15.0 g. of N-benzyl-N-[2-(3-indolyl)- 15 ethyl]-N-methylethylenediamine, M.P. 102-105 C. .(uncorn). is 2, m is 1.]

A solution of 10.13 g. (0.033 mole) of the N-benzyl- [IXa; R R R and R are H, R is CH n N'-[2-(3-indolyl)ethyl] N methylethylenediamine, prepared above, in 60 ml. of methylene dichloride was stirred and cooled while adding a solution of 4.07 g.

(0.036 mole) of a-chloroacetyl chloride in ml. of

methylene dichloride over a period of forty minutes. The mixture was allowed to stand at room temperature for an hour and a half, then refluxed for one hour and cooled. A little water and one equivalent of dilute sodium hydroxide were added, the mixture was stirred for fifteen minutes and then filtered giving a first crop of 3.6 g. of product,

Example 2.--1- [2- (S-Indolyl) Ethyl] -4-Metlzyl-2- Pi pemzinone R1, R3, R4, R5 and R are H, R2 is CH3,

C H lS CH2CH2, m iS By reducing the 1-[2-(3-indolyl)ethyl]-4-methyl-2- piperazinone benzochloride prepared above in Example 1 over 10% palladium-on-charcoal in an ethanol or Cello solve solution and isolating the product from an alkaline medium, there can be obtained 1-[2-(3-indoly1)ethyl]-4 methyl-2-pipcrazinone.

Example 3 N-Benzyl-N'- [2-(3-indolyl)ethyl] N phenylethylenediamine dihydrochloride [IXag R R R and R are H, R is C H n is 2, m is l], was prepared from 27 g. (0.13 mole) of 3-indoleglyoxalyl chloride and 58 g. (0.26 mole) of N-benzyl-N-phenylaminoethylamine in 300 ml. of tetrahydrofuran according to the manipulative procedure described above in Example 1. There was thus obtained 41.9 g. of N-benzyl-N'-(3-indolyl)glyoxalyl-N-phenylethylenediamine, M.P. 162.2162.8 C. (corr.).

Analysis.-Calcd. for C H N O N 10.57; N 3.52. Found: N 10.38; N 3.61.

The above glyoxamide (103 g., 0.26 mole) was reduced with 76 g. (2.0 moles) of lithium aluminum hydride in 2.2 liters of tetrahydrofuran according to the manipulative procedure described above in Example 1. There was thus obtained 64 g. of N-benzyl-N-[2-(3-indolyl)ethyl]- N-phenylethylenediamine dihydrochloride, M.P. 171.4- 175.4 C. (corr.).

Analysis.-Calcd. for C H N .2HCl: N, 9.50; Cl, 16.03. Found: N, 9.25; Cl, 16.12.

Example 4.1-[2-(3-Ind0lyl)Eihyl]-3-MetlzyZ-4- Phenyl-Z-Piperazz'none [XIa; R1, R3, R. and R are H, R is can, R5 is s-cm, 0,11 is (211,011,, m is 1 By reacting the free base of the N-benzyl-N'-[2-(3- indolyl)ethyl]-N-phenylethylenediamine dihydrochloride prepared above in Example 3 with a-chloro-propionyl chloride according to the manipulative procedure described above in Example 1, there can be obtained 1-[2-(3-indolyl)ethyl]-3-methyl-4-phenyl-2-piperazinone benzochloride. On reduction of the latter with hydrogen over palladium-on-charcoal according to the manipulative procedure described above in Example 2, there can be obtained 1-. [2- 3-indolyl) ethyl] -3 -methyl-4-phenyl-2-piperazinone.

16 Example 5.1-[2-(3-Ind0lyl)Etlzyl]4,6-Dimetlzyl- Z-Piperazinone [XIa; R R R and R are H, R is CH R is 6-CH C l-I is CH CH m is 1] By following the manipulative procedure described above in Examples 1 and 2 and by replacing the N-benzyl- N-methylarninoethylamine used therein with a molar equivalent amount of 1-(N-benZyl-N-methylamino)-2- propylamine, there can be obtained 1-[2-(3-indolyl)ethyl] -4,6-dimethyl-Z-piperazinone.

Example 6.1-[Z-(S-IndolyDEthyl]-3-lsopr0pyl- 4-Methyl-2-Piperazin0ne [XIZE R1, R3, R4 and R6 are H, R2 is CH3, R5 is 3-CH(CH C E; is CH CH m is 1] By following the manipulative procedure described above in Examples 1 and 2 and by replacing the a-chloroacetyl chloride used therein with a molar equivalent amount of a-chloroisovaleryl chloride, there can be obtained 1-[2(3-indolyl)ethyl]-3-isopr0pyl 4 methyl-2- piperazinone.

Example 7.1-[2-(3-lndolyl)Ethyl]-2,5-Dimethyl- 7-H0m0pz'perazin0ne [Xla; R R R and R are H, R is CH R is 2-CH C I-I is CH CH m is 2] By following the manipulative procedures described above in Examples 1 and 2, and by replacing the N-benzyl-N-methylaminoethylamine used therein with a molar equivalent amount of 1-(N-benzyl-N-methylamino)-3- butylamine, there can be obtained 1-[2-(3-indolyl)ethyl]- 2,5-dimethyl-7-homopiperazinone.

Example 8.1-[2- (3-Indolyl)Ethyl] -2,5,6-Trimethyl- 7 -H omopiperazinone [XIa; R R and R are H, R is CH R is 6-CH R is 2-CH C H is CH CH m is 2] By following the manipulative procedure described above in Examples 1 and 2, and by replacing the N-benzyl-N-methylaminoethylamine and the a-chloroacetyl chloride used therein with molar equivalent amounts of l-(N-benzyl-N-methylamino)-3-butylamine and a-chloropropionyl chloride, respectively, there can be obtained 1 [2 (3 indoly)ethyl]- 2,5,6 trimethyl 7 homopiperazinone.

Example 9.1-Phenyl-2-Piperazinone txv; R is 0 11,, R and R, are H, m is 1] To a solution of 177 g. (0.5 mole) of 1-(N,N-dibenzylamino)-2-(N-phenyl)ethylamine in 650 ml. of chloro' form was added ml. g., 1.0 mole) of oc-chloroacetyl chloride. The resulting red solution was refluxed for live and a half hours. The solvent and the bulk of the excess acid chloride were removed in vacuo and the residue dissolved in chloroform once again and extracted with dilute sodium hydroxide. The organic extracts were dried and the solvent removed leaving g. of crude 1 (N,N dibenzylamino) 2 (N o: chloroacetyl- N'-phenyl)ethylamine. The oil was taken into hot Cellosolve and the solution refluxed for four hours. The cooled solution'was dilute to a volume of 650 ml. with absolute ethanol. The resulting solution of l-benzyl-4- phenyl-3-piperazinone benzochloride was divided into two portions and each reduced over 2 g. of 10% palladium-oncharcoal under 50 psi. of hydrogen. Reduction in each case Was essentially complete in about six hours. The solutions were combined and treated with excess alcoholic hydrochloric acid and diluted strongly with ether. The resulting solid which separated was collected and dried giving 91 g. of crude l-phenyl-Z-piperazinone hydrochloride salt Was converted to the free base by treatment with alkali and the crude base sublimed at reduced pressure 17 and recrystallized from ethyl acetate giving 1-phenyl-2- Example 10 1-(4-chlorophenyl)-2-piperazinone hydrochloride [XV; R is 4-ClC H R and R are H, m is 1] was prepared from 38.7 g. (0.1 mole) of N-(4-chlorophenyl)-N',N'-dibenzylethylenediamine and 22.5 g. (0.2 mole) of oc-ClllOl'O- acetyl chloride in chloroform according to the manipulative procedure described above in Example 9. There was thus obtained the intermediate 1-(N,N-dibenzylamino) 2 [N'-(a-chloroacetyl)-N-(4-chlorophenyl)]- ethylamine hydrochloride, M.P. 161.0163.8 C. (corn).

Analysis.-Calcd. for C H Cl N QHCl: N, 6.04; Cl, 22.93. Found: N, 5.94; Cl, 22.90.

The latter was converted to the free base, quaternizcd in boiling Cellosolve and the resulting quaternary salt debenzylated over a palladium-on-charcoal catalyst according to the manipulative procedure described above in Example 9. There was thus obtained 1-(4-chlorophenyl)- 2-piperazinone hydrochloride, M.P. 192.8-194.8 C. (corn).

Analysis.-Calcd. for C H CIN OHCI: C, 48.60; H, 4.90; N, 11.34. Found: C, 48.37; H, 5.10; N, 11.05.

Example 11 l-(2,6-dimethylphenyl)-2 piperazinone hydrochloride [XV; R is 2,6-(CH C H R and R are H, m is 1] was prepared from 68.8 g. (0.2 mole) of 1-(N,N-dibenzylamino) -2-[N'-(2,6 dimethylphenyl) ]ethylamine and 45 g. (0.4 mole) of u-chloroacetyl chloride in 300 ml. of chloroform according to the manpulative procedure described above in Example 9. Catalytic debenzylation of the quaternary ammonium salt was interrupted after the uptake of one mole of hydrogen, and there was thus obtained the intermediate 4-benzyl-1-(2,6-dimethylphenyl)- 2-piperazinone hydrochloride, M.P. 248.8-264.8 C. (corr.).

Analysis.Calcd. for CmHggNgO-HCI: Cl, 10.72; N, 8.47. Found: Cl, 10.58; N, 8.50.

On continued reduction of the above 4-benzyl-1-(2,6- dimethylphenyl)-2-piperazinone hydrochloride over palladium-on-charcoal, there was obtained 1-(2,6-dimethylphenyl) -2-piperazinone hydrochloride, M.P. 224.8226.0 C. (corn).

Analysis.Calcd. for C H N O.HCl: Cl, 14.73; N, 11.64. Found: Cl, 14.66; N, 11.54.

Example 12.1-Plzenyl-6-Methyl-2-Piperazinone [XV; R2 is C5H5, R5 is H, R3 is 6-CH3, m iS By following the manipulative procedure described above in Example 9 and by replacing the 1-(N,N-dibenzylamino)-2-(N'-phenyl)ethylamine used therein with a molar equivalent amount of 1-(N,N-dibenzylamino)-2- (N-phenyl)propylamine, there can be obtained l-phenyl- 6-methyl-2-piperazinone.

Example 13.1 -Phenyl-3-Is0propyZ-Z-Piperazinone [XV; R is C H R is 3-CH(CH R is H, m is 1] By following the manipulative procedure described 18 above in Example 9 and by replacing the a-chloroacetyl chloride used therein with a molar equivalent amount of a-chloroisovaleryl chloride, there can be obtained 1- pheny1-3-isopropyl-2-piperazinone.

Example 14.1-Phenyl-3-Methyl-7-H0mopiperazionone [XV; R2 is C H R5 is H, R6 is 3-CH3, m is By following the manipulative procedure described above in Example 9 and by replacing the 1-(N,N-dibenzylamino) -2-(N'-phenyl)ethylamine used therein with a molar equivalent amount of 2-(N,N-dibenzylamino)-4- (N'-phenyl)butylamine, there can be obtained 1-phenyl-3- methyl-7-homopiperazinone.

Example 15.-1-Phenyl-3,6-Dimethyl-7-Hom0- Piperazinone [XV; R2 is C H5, R is 6-CH R iS 3-CH m iS By following the manipulative procedure described above in Example 9 and by replacement of the 1-(N,N- dibenzylamino)-2-(N'-phenyl)ethylamine and the ctchloroacetyl chloride used therein by molar equivalent amounts of 2-(N,N-dibenzylamino)-4-(N-phenyl)butylamine and a-chloropropionyl chloride, respectively, there can be obtained 1-phenyl-3,6-dimethyl-7-homopiperazinone.

Example 16.1-[2-(3-lnd0lyl)Erlzyl] -4-Phenyl-3- Pi perazinone [XVIa; R R R R and R are H, R is C H C H is CH CH m is l] A solution of 3.52 g. (0.02 mole) of the 1-phenyl-2- piperazinone prepared above in Example 9, 5.0 g. (0.02 mole) of -2-(3-indolyl)ethyl bromide and 2.8 g. (0.02 mole) of anhydrous potassium carbonate in 30 ml. of acetonitrile was refluxed for five hours, then cooled, diluted with water and basified with dilute sodium hydroxide. The mixture was extracted with chloroform and the extracts dried and evaporated. The residual brown gummy material was recrystallized twice from methanol giving 2.4 g. of l-[2-(3-indolyl)ethyl]-4-phenyl-3-piperazinone, M.P. 163.2-164.4 C. (corn).

Aizalysz's.Calcd. for C H N O: C, 75.21; H, 6.63; N, 13.16. Found: C, 75.32; H, 6.56; N, 13.06.

Examples 17-22 TABLE 1FORMULA XVIa Example R2 R R6 m 17.. P0105114 H H l 18 2,6(CHa)zC5H3 H H 1 19 05115 H 6-CH3 1 20 C5115 3CH(CH3)7 H 1 1 Cali H 3-GFls 2 22 CsH fi-CH 3-01 2 Example 23.-1-[ (3-Ind0lyl) Glyoxalyl] -4-(2-Metlzylplzenyl)Piperazine [IVa; R R R R and R are H, R is 2-CH3C6H4, m is A cold, stirred solution of 79.2 g. (0.45 mole) of 1-(2- methylphenyl)piperazine in 500 ml. of tetrahydrofuran was treated all at once with 31.2 g. (0.15 mole) of (3- indolyl)glyoxalyl chloride. There was an immediate voluminous precipitate of a white crystalline solid which was removed by filtration. The filtrate was taken to dryness and the residual light brown gum was stirred and shaken with about 700 ml. of water, 120 m1. of ethyl acetate and about 25 m1. of acetic acid. The mixture was warmed on a steamfbath'and the resulting solid was collected after cooling in an ice bath thus affording 41.5 g. (80%) of 1-[(3-indolyl)glyoxalyl]-4-(2-methylpheny1) piperazine as a near white solid. 7

2%) Examples 2491 By following the manipulative procedure described above in Example 23, substituting for the reactants used therein an appropriate (3-indolyl)glyoxalyl chloride and l-substituted piperazine, there were obtained, the' compounds of Formula IVa listed below in Table 2 where R and R in each is H and m in each is 1. The melting points are uncorrected unless noted otherwise and in the columns headed Analysis, the symbols N and N 0 represent total nitrogen and basic nitrogen, respectively.

TABLE 2FORl\/IULA IVa Example 6-C 3 2-CH3OCsH4 fi-CHa 4-CHsOC6H4 seal 10.79 N, 10. 79. 13,358--.- NB,3.59.

: 212-6 NT, 10. 74.--- NT,10.59. 2664484 {N13, 3. NB,3.59.

NT, 10. 68 NT, 10. 62. 3,3. NB,3.45.

gmgmmmmmmmmmmmm:nrnmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmm.

H NT,1o.95i NT,10.74 0 m 8 {N13, 3.59---- B, 3.58

CH3 210-22 CH3 CH3 H H H H H H H H H H See footnotes at end of table.

23 Triton B, in an appropriate organic solvent, for example ethanol, there can be obtained fi-(4-benzhydryl-1-piperazinyl)propionitrile. On hydrolysis of the latter in boiling aqueous sulfuric acid and isolating the product from a neutral medium, there can be obtained 5-(4-benzhydryl 1-piperazinyl)propionic acid, which on reaction withthionyl chloride gives 5- (4-benzhydryl-1-piperaziny1)propionyl chloride. On addition of the latter to a cold ether or 'tetrahydrofuran solution of S-chloroindolyl magnesium bromide (prepared by reaction of S-chloroindole with an ether solution of, for example, ethyl magnesium bromide),

there can be obtained 1-[3-(5-chloro3-indolyl)-3-keto-1- I propyl]-4-benzhydrylpiperazine.

Example 1 06 .1 [3- (5 -Ch lore-1 -Methyl-3-Indolyl) -3- Keto-Z -Prpyl] -4-Benzhydrylpiperazine [VIa; R is -Cl, R is (C H CH, R R and R are H, R; is CH C H is CH CH m is 1] Example 107.--1-[4-(1-Benzyl-2-Phenyl-3-Ina'0lyl)-4- Keto-J -Butyl] -4-Phenylpiperazine [VIa; R1 is H, R2 and R are C H5, R4 is C H5CH2, R5 and R are H, C H is (CH By reacting l-phenylpiperazine with acrylonitrile in the presence of a basic catalyst, for example Triton B, in an appropriate organic solvent, for example ethanol,

there can be obtained fi-(4-phenyl-l-piperazinyl)propionitrile. On refluxing the latter in anhydrous methanol saturated with hydrogen chloride, there can be obtained methyl B-(4-phenyl-l-piperazinyl)propionate. The latter on reduction with lithium aluminum hydride 'gives 3-(4-phenyl-l-piperazinyl)-1-propanol which on reaction with phosphorous tribromide gives 3-(4-phenyl-1- piperazinyl)-l-bromopropane. By reacting the latter with magnesium turnings in anhydrous ether, carbonating the resulting solution of the Grignard reagent and isolating the product from a neutral medium, there can be obtained y-(4-phenyl-1-piperazinyl) butyric acid. Treatment of the butyric acid with thionyl chloride gives -(4-phenyl-l-piperazinyl)butyryl chloride. Reaction of the latter with 2-phenylindolyl magnesium bromide prepared according to the manipulative procedure described above in Example 105 gives 1-[4-(2-phenyl-3-indolyl)- 4-keto-1-butyl]-4-phenylpiperazine. By reacting the latter with benzyl chloride in the presence of sodamide according to the manipulative procedure described above in Example 106, there can be obtained 1-[4-(1-benzyl-2- phenyl-3 -indolyl) -4-keto-1-butyl] -4-phenylpiperazine.

Examples 108-112 By following the manipulative procedures described above in Examples 105 and 106 substituting for the reactants used in Example 105 a 4-methyl-1-piperazinylbntyryl halide and an appropriate indolyl magnesium 24 R in each is CH R3, R and'R in each are H, C I-I in each is (CH and m in each is 1:

TABLE it-FORMULA VIa Example R1 R4 108 6-n-C4H9O 4-CH3SCaH4CHzCHg.

5,6,7-tri-CHaO 4-I1-C4HoOCuH4CHzCHz. H l 3-HOC9H4CH1CH2. H CnHsCH-CHCHg.

Example 113.1-[2-(3-Ina'0lyl)-1-Ket0ethyl]-4 Phenylpiperazine [VHa; R R R R and R are H, R is C H n is 2, m is 1] To a cold, stirred solution of 22.5 g. (0.132 mole) of indole-3-acetic acid and 13 .3 g. (0.132 mole) of triethylamine in 800 ml. of acetone was added 18.1 g. (0.132 mole) of isobutyl chloroformate and the solution was stirred at 10 C. for twenty rninntes. A solution of 21.4 g. (0.132 mole) of l-phenylpiperazine in a little acetone was added, and the solution stirred for an hour and forty-five minutes at room temperature.

7 V The insoluble material was removed by filtration, the filtrate taken to dryness, and the residue redissolved in methylene dichloride and washed with water and dilute sodium hydroxide. The organic layer'was dried, the solvent re- 7 moved and the residue recrystallized from ethanol giving 4.39. Found: N 12.91; N 4.39.

5.4 g. of 1-[2-(3-indolyl)-1-ketoethyl]-4-phenylpiperazine, M.P. 179.4181.6 C. (corr.).

Analysis.Calcd. for C2 H21N OZ N N Example 114 1-[3-(3 -indolyl) 1 ketopropyl]-4-phenylpiperazine R1, R3, R4, R5 and R6 are H, R2 is C H5,

halide and substituting for the methyl iodide used in 7 C H is CH CH m is 1] was prepared from 25 i g. (0.132 mole) of indole-3-propionic acid, 13.3 g. (0.132 mole) of triethylamine, 18.1 g. (0.132 mole) of isobutyl chloroformate and 21.4 g. (0.132 mole) of l-phenylpiperazine in 800 ml. of acetone according to the manipulative procedure described above in Example 113. The product was recrystallized from ethanol giving 27.5 g. of 1-[3-(3-indolyl)-1-ketopropyl]-4-phenylpiperazine, M.P. 136.2137.4 C. (corr.).

Analysis.Calcd. for C H N O: N 12.42; N 4.14. Found: N 12.52; N 4.18.

Example 115 Examples 116-126 By following the manipulative procedure described above in Example 113, substituting for the reactants used therein an appropriate 3-indole-lower alkanoic acid and l-substituted-piperazine, there were obtained the compounds of Formula VIIa listed below in Table 5 in which R R R and R in each are hydrogen and m 'in each is 1. The melting points are uncorrected unless noted otherwise.

TABLE 5-FORMIULA.

Analysis Example R 7R; CHE M.P., C.

Oalcd Found 3-CH3OC CH1 2010.151. .omcr V 2-OH3CJD ,CBzCFL, 11 56 N n 63 T r z-cmocfim cmcrn 173. -6.0 g 339 Cm Fl z (0E2) 2-CH300aH4 (CH2): 129-32 3-CH OCH1 (SE9 01W CHQOH: 169-72 N 11.56."- N 11.04

C, 70.20-"..- C, 69.00 124 G-CHsO Z-CHsOCaH-i CHjCHg 120. 5-2. 0 {IL 6.92 H, 6.77

, N, 10.68 N, 10.30 125 5,6-(ll-GH30.. 3-0106111 CH1 1% 5,6061130 a. 05115 CHzCHg 178-80 1 Corr.

Example 127.--1-(Z-Indolylcarbonyl)-4Phenylpiperazine [Vllbg R R R and R are H, R is C l-I n is 1, m is 1] By following the manipulative procedure described above in Example 113, replacing the indole-3-acetic acid used therein with a molar equivalent amount of indole-Z- carboxylic acid, there can be obtained 1-(2-indolylcarbonyl) -'4-phenylpiperazine.

Example 128..-1-(3-1ndolylcarbonyl) -4 Phenylpz'perazine IVIICZ; R1,,R3, R4, R5 and R5 are H, R C H n is 1, m is 1] By following .the manipulative procedure described aboveabove in Example 113, replacing the indole-3-acetic acid used therein with a molar equivalent amount of indole-3-carboxylic acid, there can be obtained 1-(3-indolylcarbonyl)-4-phenylpiperazine.

Examples 129-137 PREPARATION OF FINAL PRODUCTS Example 138.-1-[2-(3-lnd0lyl)Etlzyl]-4- Phenylpiperazine V [Il; R1, R3, R4, R5, R5 and X BIB H, R2 is C5H5, I1 is 2, m is l] A mixture of 5.6 g.(0.025 mole) of S-indolylethyl "bromide, 4.1 g. (0.025 mole) of l-phenylpiperazine and 2.1 g. (0.025 mole) ofsodium bicarbonate in 30 ml. of absolute ethanol was refluxed with stirring for six hours. The bulk of the solvent was removed in vacuo, water Was added along With sufiicient dilute sodium hydroxide to render the mixture alkaline, and the mixture was extracted with ether. The organic extracts were dried, the solvent removed and the residue recrystallized from acetone to give 1.4 g. of 1-[2-(3-indolyl)ethyl]-4- phenylpiperazine, M.P. 131.6-136.0 C. (corn).

Analysis.Calcd. for C H N C, 78.65; H, 7.59 N, 13.76. Found: C, 78.74; H, 7.74; N, 13.50.

Examples 139-142 By following the manipulative procedure described above in Example 138 substituting for the reactants used therein an appropriate (3-indoiy1)-loWer-alkyl bromide and 1-substituted-piperazine, there were obtained the (3- indolyl) -lower-alkyl-4-substituted piperazines or" Formula Ia listed below in Table 7, where R;,, R R R and X in each is H, n in each is 2 and m in each is 1. All melting points are corrected.

TABLE 7FORlVIULA Ia Analysis Example R1 R5 M.P., "O.

Calcd. Found 0, 70. O, 70.80. 139 H 443105131 185.2- E, 6.5 H, 6.51.

186.8 N, 12. N, 12.23. C, 7s. 0, 78.62. 140 H 4015130 11, 1478- H, 7.89 H, 7.61.

154.8 N, 13. N, 12.91. 0, 75. C, 75.91. 141 5-OH3O--- 1-011mm, 108.6- E, 7.79 H, 7.88.

111.0 N, 12.03.-." N, 11.93. 0, 0,6557. 142 H OQH5CH=CHCHZ- 258.2- H, H, 7.01. 263.6 N, N, 9.98.

Formula VIIa listed belowin Table 6 where R R R and R in each is H and n in each is 2: Examples 143-147 TABLE 6-FORMULA VIIa By following the manipulative procedure described Example R1 m above in Example 138, replacing the 3-indolylethyl bromide used therein with a molar equivalent amount of a 4-C2H5 CsHsCHgCHz 1 MCHQQCH ,GHESOEHACECHI 1 (1 indolyl) lower alkyl halide and the 1 phenylprperazme 7-(CH3)3C 3,.rO CH20OEH3CHBCH2 H 2-C5H4N H 2pyrimidyl 5,5-di-CH3O 2-pyrazinyl 5,6 OCH;O 2-thiazolyl 5,6 O CHgCHgO- 2-(1,3,5-triazi11yl) 2 used therein with a molar equivalent amount of an appropriate l-substituted-piperazine or l-substituted-homopiperazine, there can be obtained the compounds of Formula 10 listed below in Table 8 where R R and R in each is H.

Examples 148-152 TABLE 9FORMULA Ib Example R2 R4 C EE; m

4-010 114 H C 1 2-C5H4N O CH CH U, 2 Z-pyrimidyl--- CaHsCHz (CH2)3 2 2-pyrazinyl C611 (CH 1 1 2-thiaz0lyl O5H CHCHOH (CH2); 2

Examples 153-158 By following the manipulative procedure described above in Example 138 substituting for the reactants used therein an appropriate (3-indolyl)-lower-alkylhalide and l-methylpiperazine, there can be obtained the 1-[(3- indolyl)-lower alkyl]-4-methylpiperazines of'Formula Ia listed below in Table where R R R R and X in each is H, R in each is CH and m in each is 1.

TABLE 10-FORMULA Ia Frozen-uexcess lithium aluminum hydride then destroyed by the 28 Example 159.-1-[2-(3-Indolyl)Ethyl]-4-(2-Methylphenyl)Piperazine R1, R R R R 'and X are H, R is 2-CH C H n is 2, m is l] A solution of 41.5 g. (0.12 mole) of 1-[(3-indolyl)- glyoxalyl]-4-(Z-methylphenyDpiperazine in 250ml. of

. tetrahydrofuran was added over a ten minute period to a stirred suspension of 27 g. (0.72 mole) of lithium alumi- V num hydride in 300 ml. of tetrahydrofuran. The mixture was'refluxed and stirred for six and a half hours and the dropwise addition'of 140 ml. of 10% sodium hydroxide solution. The mixture was filtered, the insoluble material was washedwith boiling chloroform, and the filtrate dried over anhydrous sodium sulfate and-concentrated to dryness.- The residual light orange oil was crystallized from a benzene-hexane mixture giving 28.5 g. of 1-[2-(3- indolyl) ethyl] -4-(2-methylpheny1)piperazine, M.P. 124.2- 126.4 C.

Analysis.-Calcd. for C H ,N, c, 78.96 H, 7.89; N, V

13.16. Found: C, 79.05; H, 7.85; N, 13.10. v

1 [2 (3-indolyl)ethy11-4-(2-methylphenyl) piperazine can be reacted with hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, acetic acid,- citric acid, tartaric acid, quinic acid, methyl iodide, methyl bromide, ethyl bromide, allyl bromide, benzylchloride, 2- chlorobenzyl chloride or methyl p-toluenesulfonate to give the hydrochloride, hydrobromide, hydriodide, sulfate (or bisulfate), phosphate (or acid phosphate), acetate, citrate (or acid citrate), tartrate (or bitartrate), quinate, methiodide, methobromide, ethobromide, allobromide, benzochloride, 2-chlorobenzochloride, or metho-p-toluenesulfonate salts, respectively.

1 [2 (3-indolyl) ethyl] -4-(2-methylphenyl)piperazine can be reacted with arsenic acid to give the arsenate salt which can be useful as acharacten'zing derivative.

1 [2 -(3-indolyl)ethyl] -4-(2-methylphenyl)piperazine,

in the form ,of its hydrofluoride salt can be converted to the hydrochloride salt by passing an aqueoussolution of the former over an ion-exchange resin saturated with chloride ions, for example Rohm and Haas Amberlite IRA-400 resin.

Examples 160-224 By following the manipulative procedure described E I R O H above in Example 159, substituting for the 1-[(3-indolyl)- xamp e v 3 glyoxalyl]-4-(2-methylphenyl)piperazine used therein the CH2 ('CH) 1 [(3 -indolyl)glyoxalyl] 4-substituted-piperazines pre- 154 CHwHm 5i pared above in Examples 24-88 (Table 2), the respectlve Elgggg gmy Egg? 1-'[2-(3-indoly1)ethyl]-4-substituted-piperazines of For- 157 3 2 mula Ia listed below in Table 11 were prepared. All 158 Q G wl e mmelting points are corrected unless noted otherwise. In

each example R and R are H, n is 2 and m is 1.

.TABLE lit-FORMULA Ia Analysis Example Rs/Rz Bil/R4 X Salt M.P., C.

Calcd Found N N,12.99. }H 21301 27ao-sas D 1% '22 ,11. }11 21101 mas-71.4 011mm 0,78. 0,7920. }E 163. 8-6.2 {11,7 11,7.59. 7 '19 H H 1 1 H 111. 4-1.2 11,7 51 11,745. 164 g g 3.2 8 gn,8.24. 5.1 .7534.

l-onsoourrn- H V i {gg s ga sg 165 H H- H 159.260.6 N,11.88 N,11.62. H V {o1,10.02. 1, 2. 166 6-CH3O H H 7 137.4-9.e 11,7 11.7.42. H N,l2.6l.

s1 TABLE 11-FORMULA Ia-Oontinued Analysis Example Ra/R: 7 Ra/R4 X Salt M.P.,C.

Caled Found 213 aeoomcmo H O H H 214 5,6rdi-OH3O on.

20113068114 H }H 2HCl 217.4-208 215 sear-c1130 H 2-C2H5OC5H4 H }H 216 sear-&0 CH3 2-OH C H H 217 sear-c1130 on.

V :wHacam }H 21101 210. 2-3. 8

21s sear-c1130 30153008114 H }H 2HC1 1s2.e4.2

219 sear-onto H 2,6(CH3)20H3 n i 220 ae-oomo CH3 a a la 2 a }H 2 2.. aaaas a 2 a a P1 a s-onaooflrn H Uncorr.

Example 225 CH C H R R R and R are H, X is OH, n is 2, m

is 1] was isolated as a by-product in the preparation of 1 [2 (5,6-dimethoxy-3-indolyl)ethyl]-4-(4-methylphenyl)piperazine (Example 184) from 33 g. (0.081 mole) of 1 [(5,6 dimethoxy 3 indolyl) glyoxalylIA-(Z-methylphenyl)piperazine and 10 g. (0.263 mole) of lithium aluminum hydride in 1100 ml. of tetrahydrofuran according to the manipulative procedure described above in Example 159. The crude product isolated from the reaction mixture was recrystallized from methanol to give a first crop of g. which on recrystallization from ethyl acetate gave 16.2 g. of l-[2-(5,6-dimethoxy-3-indolyl)ethyl]- 4-(4-methylphenyl)piperazine, M.P. l3413-7 C. (uncorr.) (Example 184). if

Ana lysis.Calcd. for C H N O N, 11.07. Found: N, 10.87.

The filtrate from the main crop on concentration afforded a second crop of 2.5 g. of crystals, M.P. 190- 196 C. (uncorr.). It was recrystallized from acetone to give 2 g. of 1-[2-(5,6-dimethoxy-3-indolyl)-2-hydroxyethyl] -4- (4-methylphenyl pip erazine, M.P. 1 93 .2-19 8.0

C. (corn).

Analysis.Calcd. for C H N O C, 69.85; H, 7.39; N, 10.63; 0, 12.14. Found: C, 70.04; H, 7.16; N, 10.55; 0, 12.08.

Example 226 .-1 -[2-(5-H ydr0xy-3-Ind0lyl )Ethyl] 4-(4- Methylphenyl)Piperazine [111; R1 is 5-HO, 4'CH3C H4, R3, R4, R5, R and X areH,nis2,mis1] residual solid was recrystallized from ethanol to give 1- [2- (5 hydroxy 3 indolyl) ethyl] .-4-(4-methylphenyl) piperazine, M.P. 193.2-195.8 C. (corr.).

Analysis.-Calcd. for C H N O: C, 75.19; H, 7.51; N, 12.53. Found: C, 75.18; H, 7.75;-N, 12.16.

A small amount of the base was converted to the methane-sulfonic acid salt. The latter was recrystallized from an acetonitrile-ethyl acetate mixture to give 1-[2-(5- hydroxy 3-indolyl)ethyl]-4-(4-methylphenyl)piperazine methanesulfonate, M.P. 233-235 C. (uncorr.).

Analysis.Ca1cd. fOI' C22H29N304S: N, 9.74. Found: N, 9.42. 7

Example 227 1-[2-(5-hydroxy 3 indolyl)ethyl] 4-phenethylpiperazine R1 is S-HO, R2 is C6H5CH2CH2, R3, R4, R5, R3 and X are H, n is 2, m is 1] was prepared from 1.9 g. (0.004 mole) of the 1-[2-(5-benzyloxy-3-indolyl)ethyl]- 4-phenethylpiperazine prepared above in Example 173 according to the manipulative procedure described above in Example 226. The crude product was recrystallized from ethyl acetate to give 1.4 g. of 1-[2-(5-hydroxy-3-indolyl)- ethyl] 4 phenethylpiperazine, M.P. 198.0- 201.6" C. (corr.).

Analysis.Calcd. for C22H27N30Z C, 75.61; H, 7.79; N, 12.03. Found: C, 75.46; H, 7.63; N, 11.83.

Example 228.-1-[2-(1-Methyl-3-Ind0lyl)Ethyl]-4 Phenylpiperazine [1.1; R1, R3, R5, R6 and X a... H, R c n R. is CH3, n is 2, m is 1] To a stirred solution of 0.83 g. (0.036 atom) of sodium in 300 ml. of liquid ammonia under nitrogen was added 10.0 g. (0.033 mole) of l-[2-(3-indolyl)ethyl]-4-phenylpiperazine prepared above in Example 138. The mixture was stirred for about one hour during which time the indole dissolved completely. To the solution was then added a solution of 5.23 g. (0.036 mole) of methyl iodide in 100 ml. of ether and an additional 500 ml. of liquid ammonia. The mixture was stirred for three hours and a then allowed to stand at room temperature for two days.

An additional 300 ml. of ether'was added and the unreacted sodamide destroyed by the addition of ml. of water. The organic layer was separated, dried over anhydrous sodium sulfate and the solid that separated from the dried solution was collected and extracted with chloroform. The chloroform solution was evaporated and the residual solid recrystallized from methanol giving 4.7 g. of 1-[2-(1-methyl-3-indolyl)ethyl] 4 phenylpiperazine, M.P. 93.8-95.6 C. (corn).

Analysis.Calcd. for C H N N 13.16; N 8.78. Found: N 12.91; N 8.89. V V

33 Example 229 1-[2-(1,2-dimethyl 5,6 methylenedioxy 3 indolyl)- R R and R in each is H, n in each is 2'and m in each is 1:

TABLE 12-FORMULA Ia ethyl] 4 (2 methoxyphenyl)piperazine [Ia;'R is 5,6- OCHZO, R2 is 2-CH3OC6H4, R3 and R4 are CH3, R5, R6 and X are H, n is 2, m-is 1] was prepared from 8.0 g. (0.020 mole) of 1-[2-(2-methyl 5,6 methylenedioxy-3- indolyl)ethyl] 4-(2-methoxyphenyl)piperazine prepared above in Example 220, 0.5 g. (0.02 atom) of sodium in 400 ml. of liquid ammonia, and 3.5g. (0.024 mole) of methyl iodide using the manipulative procedure described above in Example 228. There was thus obtained 7.8 g. of 1-[2-(1,2-dimethyl 5,6 -methylenedioxy 3-indo1yl)- ethyl] 4 (2 methoxyphenyhpiperazine, M.P. 118.2- 1l9.6 C. (corn).

Analysis.Calcd. for C I-1 N C, 70.73; H, 7.17; N 6.77. Found: C, 70.93; H, 7.50; N 6.77.

Example 230 1- [2-( 1-benzyl-2-methyl 5,6-methylenedioxy-3 -indolyl) ethyl] 4 (2 methoxyphenyl)piperazine Ha; R is 5,6- OCHzO, R2 is 2-CH3OC5H4, R3 is CH3, R4 is C6H5CH2, R R and X are H, n is 2, m is 1] was prepared from 8.0 g. (0.020 mole) of 1-[2-(2-methyl-5,6-methylenedioxy-3-indoiy1)ethyl] 4 (2-methoxyphenyl)piperazine prepared above in Example 220, 0.5 g. (0.022 atom) of sodium in 400 ml. of liquid ammonia and 4.5 g. (0.026 mole) of benzyl bromide using the manipulative procedure described above in Example 228. There was thus obtained 3.0 g. of 1-[2-(1-benzyl-2-methyl 5,6 methylenedioxy-3indolyl)ethyl] 4 (Z-methoxyphenyl)piperazine, MP. 1692-1702 C. (corn).

Analysis.Calcd. for C H N O C, 79.51; H, 6.88; N, 8.69. Found: C, 79.55; H, 6.71; N, 8.72.

CH3 CH(CH3); OH.

CH20:E(I:(CH3)2 CH2CH(CH3)z OH.

4-(CH3)ZCHOHZCQH4CHZ 0550112011 Z-pyrimidyl H H 2-pyrazinyl H H. 2-thiazolyl CH; OH. 2-(1,3,5-triazinyl) H H.

Example 244 .1 [3- (5 -Chl0r0-3-I ndolyl -Pr0pyl] 4 -Benzhydryl pi perazine By reacting the 1-[3-(5-chloro 3 indolyl) 3-keto-1- propyl] -4-benzhydrylpiperazine prepared above in Example 105 with lithium aluminum hydride in an appropriate organic solvent, for example ether or tetrahydrofuran, according to the manipulative procedure described above in Example 159, there can be obtained 1- [3-(5-chloro-3- indolyl)-1-propyl]-4-benzhydrylpiperazine.

Example 245. 1- [3-(5-Chloro-3-lndolyl) -3-Hydr0xy-1- Propyl]-4-Benzhydzylpiperazine By reacting the 1-[3-(5-cl1loro 3 & indolyl) 3-keto-1- propyl] 4-benzhydrylpiperazine prepared above in'Example 105 with sodium borohydride in an appropriate organic solvent, for example ether, tetrahydrofuran or methanol, using the manipulative procedure described above in Example l'59 for isolating the "product, there can be obtained 1-[3-(5 chloro 3 indolyl) 3 hydroxy-lpropyl] -4-benzhydrylpiperaz ine.

Examples 246-252 By reacting the compounds prepared abovein Examples 106412 with lithium aluminum hydride according to the manipulative procedure described above in Example 105, there can'be obtained the respective compounds of Formula Ia listed below in Table 13vvhere R and R in each is H, X in each is OHand m in each is 1:

TABLE 13-FORMULA Ia Example R1 R5 R /R; l Cn-lHfln-i 247. H CaFl's 248 6-I1-C4HBO CH:

249 5,6,7-tri-CH3O on. H

250. H OFF.

251. H CH.

252 a,4,somo)3o5momo om Examples 231-243 Example 253.-1-'[2-(3-Indolyl)Eihyl]-4- Phenylpiperazine [Ia; R R3,R1, R R and X are H,"R is C H n is 2, m is 1] By reacting the 1- [2-(3-indolyl)-l-ketoethyl] -4-phenylpiperazine obtained above in Example 113 with lithium aluminum hydride in an appropriate organic solvent, for

pounds of Formula Ia listed below in Table 12 where example ether or tetrahydrofuran, according to the manipulative procedure described above in Example 159,

there can be obtained 1-[2-(3-indolyl)ethyl]-4-phenylpiperazine. v

Example 254 1-[3-(3-indolyl)propyl]-4-phenylpiperazine [Ia; R R

[(3 indolyl) a keto-lower-alkyl]-4-substituted-piperazines prepared above in Examples 116 to 126, there were obtained the respective compounds of Formula Ia listed below in Table 14 in which R R R R and X in each are H and m in each is 1. The melting points are corrected unless noted otherwise.

TABLE 14-FORMULA Ia Analysis Example Rr/R: Gil-IEIn-Z M.P., C.

' Calcd. Found 256... H T 12.53---. NT, 1234 v }CH1 146.4-715 FE 836m" NB, 8 26 H 011201120 nae-1; ala

263 6-CH O 60H) "}0H2OHz. 1531-50 1% ll gl 265 o.eo.5s 0, 60.66.

------ }OH;- wees-9.2 H, s.24 11.6.01.

06H }oH,oH,- nae-4.2 N311 1 Hydrochloride salt.

In is 1] was prepared from g. (0.060 mole) of.1-[3'-(3- indolyl) 1 ketopropyl] 4 phenylpiperazine, prepared above in Example 114, and 10.8 g. (0.360 mole) of lithium aluminum hydride in 600 ml. of tetrahydrofuran according to the manipulative procedure described above in Example 159. The crude product was recrystallized from absolute ethanol to give 10 g. of l-[3-(3-indolyl)propyl]- 4-phenylpiperazine, M.P. 126.6-127.8 C. (corn).

Analysia Calcd. for C l-Ig N z N 13.15; N 8.76. Found: N 13.11; N 8.50.

Example 255 1-[3-(1-indo1y1)propyl]-4-phenylpiperazine [Ic; R R R5, R5 X are H, R2 is C6H5, C 1H2 2 is CH2CH2, m is 1] was prepared from 37 g. (0.111 mole) of 1-[3-(1- indolyl)-l-ketopropyl]-4-phenylpiperazine prepared above in Example 115 and 16.9 g. (0.444 mole) of lithium aluminum hydride in one liter of tetrahydrofuran according to the manipulative procedure described above in Exam,-

Example 2 67.1-(2-Ind0lylmethyl) -4-Phenylpiperazine [112; R R R R and X are H, R is C H n is 1,

m is 1] By reacting the l-(2-indolylcarbonyl)-4-phenylpiperazine prepared above in Example 127 with lithium aluminum hydride in an appropriate organic solvent, for example ether or tetrahydrofuran, according to the manip- 40 ulative procedure described above in Example 159, there can be obtained 1-(2-indolylmethyl)-4-phenylpiperazine.

Examples 268-277 By reacting the compounds prepared abovein Examples 128-437 with lithium aluminum hydride in an ap propriate organic solvent, for example ether or tetrahydro furan, according to the manipulative procedure described above in Example 159, there can be obtained the respective compounds of Formula Ia listed below in Table 15,

where R R R R and X in each is H:

TABLE l5-FORMULA Ia ple 159. The crude product was recrystallized from methanol to give 19 g. of 1-[3-(1-indolyl)propyl] -4-phenylpiperazine, M.P. 96.7-98.4 C. (corr.).-

Analysis.Calcd. for C H N C, 78.96; H, 7.89; N 8.78.. .Found: C, 78.81; H, 7.65; N 8.47.

Examples 256-266 By following the manipulative procedure described above in Example 254, substituting forthe l-[3-(3-indo lyl)-1-ketopropyl] 4-phenylpiperazine used therein the 1- Example 278.1-(3-Ind0lylmethyl) -4-Phenylpiperazine [Ia; R1, R3, R4, R5, R3 and X are H, R2 is C5H5, n and m are 1] A solution of 6.25 ml. of formalin and 13.3 g. (0.082 mole) of l-phenylpiperazine in 100 ml. of dioxane was cooled to 5-10 C.,-and a solution of 9.0 g. (0.077 mole) of indole in 100 ml. of dioxane was addedwith stirring over a period of about twenty minutes. When about half of the indole'solution had been added, about 20 m1. of: glacial acetic acid was poured into the reaction mixture.

Example 279 1-(5,6 dimethoxy-3-indolylmethyl)-4-phenylpiperazine [Ia; R is 5,6-di-CH O, R is C H R R R R and X are H, m and n are 1] was prepared from 5.0 g. (0028 mole) of 5,6-dirnethoxyindole, 4.9 g. (0.03 mole) of N- phenylpiperazine and 2.2 ml. of formalin and 5 cc. of glacial acetic acid using the manipulative procedure described above in Example 278. The product Was recrystallized from benzene giving 4.7 g. of l-(5,6-dimethoxy-3-indolylmethyl)-4-phenylpiperazine, M.P. 159.2-160.2 C. (com).

Analysis.-Calcd. for C H N O N 1196; N 7.97. Found: N 11.36; N 7.76.

Examples 280-288 By following the manipulative procedure described above in Example 278 and by replacing the l-phenylpiperazine used thereinwith arr'appropriate.l-substitutedpiperazine or 1-substituted-homopiperazine, therecanbe obtained the compounds of. Formula Ia listed below in Table 16 where R R R R and X in each is H, and n in each is l: a

TABLE 16FORMULA Ia Examples 290-301 By reacting the compounds prepared above in Examples 4, 5, 6, 7, 8, 16 and 1722 with lithium aluminum hydride in an appropriate organic solvent, for example ether or tetrahydrofuran, according to the manipulative procedure described above in Example 159, there can be obtained the respective compounds of Formula Ia listed below in Table 17 where R R and X in each is H:

TABLE l7-FORMULA Ia Example R1 R R5 Rs. in. .m

H, 2 1 H 2 1 H 2 1 H 2 2 H 2 2 H 2 1 H v 2 1 H '2,6-(CH3)2C&H3---- H H- 2 1 H CsHa H 6-CHa 2 1 H CuHs 3-CH(CHa)g H 2 l H CAPT T-T 3-0113-.- 2. 2. H CKFT G-CFI: S-CHQ-.- 2 2 lyl 2 -Eth-yl propyl }-4-Methy 1 pi perazine By reacting the 1-{3-[2-(4-methylmercaptophenyl)-3- indolyl] 2 ethylpropyl} 4 methylpiperazine prepared above in Example 158 with one molar equivalent of peracetic acid (hydrogen peroxide dissolved in glacial acetic acid) in an appropriate organic solvent, for example ethanol, at a temperature between about 0 C. and about 25 C., there can be obtained l-{3-[2-(4-methylsu1finylphenyl) -3-indolyl]-2-ethylpropyl}-4-methylpiperazine.

Example R1 R: 'm Examples 303-310 C CH By following the manipulative procedure described fi fi gg 40 above in Example 302, substituting for the 1-{3-[2-(4- ggigt cg g li CHCH methylmercaptophenyl) 3 indolyl] 2 ethylpropyl}-4- j j 1 methylpiperazine used therein the compounds prepared g-py p i above in Examples 174, 175,. 188, 23 5, 236,248, 270 and jgfigigfiyi; 2 271, there can be obtained the respective compounds of 2-(1,3,5-triazinyl) 2 Formula Ia listed below in Table 18 where R R and 0 R areHandm ineachis 1:

TABLE 18-FORMULA Ia Example R1 R: R4 X C n-lHln-Q 303 5-CH SO 504 0 }H H CH2 5- 305 i g g ii" }H n H CH2. 1- a 306 lomsooflmml H OH(0H3)CH2CH2OH 4'OICGHACH2 OH OH!- 307 6-(OH8)2CHSO OH (.CHMOH 9 "t iitiiidil- (CHM- 309 5-(0113 H OH -CHaSOCaEhCHgCHg- 10 (i-CHAQHzl-r OH 4-(OH3) GHSOC@H,OH,OH,

Example 289.--1-[2-(3-Ind0lyl)Ethyl] -4- Meth ylpiperazz'ne 7 [1(1; R1, R3, R4, R5, X are H, R2 is CH3, nis 2,

' m is 1] 20 C. and about 100 C., there can be obtained 1-{3-[2- (4-methylsulfonylphenyl) 3 indolyl] 2-ethylpropyl} 4- methylpiperazine.

. 3,135,794 a9 4o Examples 312-319 Analysis.-Calcd. for C H N O N 14.52.; N 9.68. Byfollowing the manipulative procedure described 1432; above in Example 311 substituting for the 1-{3-[2-(4- i Examples 322425 methylmercaptophenyl) 3 indolyl]-2-ethylpropyl}-4- V Y methylpiperazine used therein the compounds prepared 5 By following the manipulative procedure described above in Examples 174, 175, 188, 235, 236, 248 270 and above in. Example 320, substituting for the' 1-[2-(3- 271', there can be obtained the respective compounds of indolyl)ethyl]-4-benzylpiperazine' used therein the com-- Formula Ia listed below in Table 19 where R R and R pounds prepared above in Examples 239, 244, 245 and in each is H and m in each is 1: 246, there canbe obtained the respective compounds of TABLE 19-FORMULA Ia i i Example V V R1/R: V V V V V V 7 R4 X Cl11 1n H 313 scmso.

comma..." H 314 ig gg }H H CH. U 3 g a 4 315 ve-cmso.

omormomomon H 316 Z% }4-FC5H4CH:; OH on, 2 8 l 35525911133111::::::"::::::W 318 s-(cHmcu gggasg omromcm H 4-(oumonsmoamomcm H Example 320. 1 [2 (3 lnd0lyl)Ethyl]Piperazine Formula Ia' listed below in Table Where R R R and R in each is H and m in each is 1:

Ha; R1, R2, R3, R4, R5, R5 and X are H, m is 1, n is TABLE 2O FORMULA I 1-[2-(3-indolyl)ethyl]-4-benzyl piperazine (18.5 g., E I R a R X Ck H 0.058 mole) prepared from the 1-[(3-indolyl)glyoxalyl]- xamp e I 4-benzylpiperazine prepared above in Example 90 was 322 S43E30 COHECECHLHH 0H dissolvedin absolute ethanol and reduced over 10% pal- 2 3 Eggs):- 2):. ladium-on-charcoal under about 50 pounds p.s.1. of hydro- 325 5-01 cm .0H (0H,.

gen with warming. When reduction was complete, the catalyst was removed by filtration, the filtrate taken to dryness and the residue recrystallized from ethyl acetate had been admmlstered produced potentlatlon ofhexoglvmg of 1-[2 (3 lndolyl)ethyl]plperazme barbital-induced sleeping time. They produce tranquil- The compounds of Formulae la, b and 0 when admin- 149345200 (corny 40 ization of mice when given orally as shown by'th'eir Analysls calcd' for CHHNNS: 1833; reaction to being touched lightly on the vibrissae (head Found: NE, withdrawal reflex); When administered orally in mice, they showed adrenolytic activity as evidenced'by antago- Example321 nism of the pressor elfects of epinephrine. Further evidence of tranquilizing and C.N.S. depressant activity for R gi gi g g ig g k kl gl z ggg gz g 5 V the compounds was shown by overt behavior studies in 11 iS.2] was im 'paigd Om 17 7 g. of 1 [2 5 monkeys (oral) 1n WhlCh the compounds produced a 1 d7 tam ng etfect, sedat1on, skeletal muscle relaxation, hypooxy-If-mdolyDethyl] 4 benzy piperaz ne, prepare thenma and catalepsy.

above Example R i l s camisd out accord '50 Oral toxicity studies in mice have shown that the LD g to the manipulative P t d descliibed' abgve. i l of the compounds is in the range from about 110 mgjkg. Example The Product was fecrystalhled from bell" jj j to about 4000 mg./kg. where LD is defined as the dose zene giving Y- y y i fatal to 50% of the animals at that particular dose level. piperazine, M'.P. 109.6-111.4 C. (corn). jj In Table 21 below'which summarizes the data so-ob- TABLE 21' H H.P.T. H.W.R. A.S.T. LDm Overt Behavior Example EDgo E1350 EDso (mg./kg.) MILD.

. e/ e/ (v/ -I e.)

S, T and 64. 13. 8:1:3. 9 18. :5, 1 13. 4:!;2. 1 440 S, T, C and H, 32.

8.2;|=1.5 9. 15:2. 1. 65:]:8. 4 V 3, 090 T, C and H, 8. 4. 7:1;1. 0 13. 413.5 28;|;5.6 S;lmd H, 8; R and 2. 6.6i1.4 6. 4:l:1.6 11.313. 5 S,0T1and H, 4; R and 8. Oil. 6 40=l=12 40:1:5, 2 S and H, 8; C, 64. 5. 41:0. 7 8 0:1:1. 9 53. 5=b8 8 S, T, H and C, 16. 6. 811. 6 6 5i1.2 7'-2 8. 812. 6 22:1:7. 6 575:10 2 S, T, C and H, 64. 5. (iii). 7 6. 411. 8 38:1:14 7 S, T, C and H, 32. 3. 25:1. 2 13. 4:l:4. 0 735:20 5 S, T and H, 16. 8.05:2. 7 43i15.0 883:8 1 T, S and H, 64. 4.95:1.1 4 93:0,.84 5. 55:2 1 T, S, O and H, 32. 5. 2:|:1. 8 10.15:];1. 6 1603:28 9 T, S, C and H, 16. i 13. 2:1:3. 7 613114. 2 254:);30 9

7. 7=b1. 1 14. 613. 1 T, O and H, 16. 5. 0:1:L3 128 66. 5:118. 7 S. T. R and H, 64 3. 7:l=0. 57 6. 5:112. 1 97:1:15. 6 T, O and H, 4.

istered orally to mice to which 40 mg./kg. of hexobarbital 

1. A MEMBER OF THE GROUP CONSISTING OF (A) COMPOUNDS OF THE FORMULA 